Volume 8, Issue 2, May – June 2011; Article-012
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Review Article
SOLID DISPERSION: STRATEGY TO ENHANCE SOLUBILITY
Rahul M. Patil*, Ajim H. Maniyar, Mangesh T. Kale, Anup M. Akarte, Dheeraj T. Baviskar
Department of Pharmaceutics, KVPS Institute of Pharmaceutical Education, Boradi, Shirpur- 425 428, (M.S.), India.
Accepted on: 08-03-2011; Finalized on: 28-05-2011.
ABSTRACT
The solubility behavior of drugs remains one of the most challenging aspects in formulation development. With the advent of
combinatorial chemistry and high throughput screening, the number of poorly water soluble compounds has dramatically increased.
Although solid solutions have tremendous potential for improving drug solubility. This article reviews the various preparation
techniques for solid dispersion and gives some of the recent technology transfers. Some of the important practical aspects to be
considered for the preparation of solid dispersions, such as selection of carrier and methods of physicochemical characterization.
New manufacturing processes to obtain solid dispersions have also been developed to reduce the drawbacks of the initial process.
In this review, it is intended to discuss the recent advances related on the area of solid dispersions. Solid dispersion technologies are
particularly promising for improving the oral absorption and bioavailability of BCS Class II drugs. The focus of this review article on
the method of preparation, carrier used, characterization, advantages, disadvantages and the application of the solid dispersion.
Keywords: Solid solutions, solubility, solid dispersions, carrier, bioavailability.
1. INTRODUCTION
Oral drug delivery is the most popular, simplest and
easiest way of administering drugs. Because of the
greater stability, smaller bulk, accurate dosage and easy
production, solid oral dosages forms have many
advantages over other types of oral dosage forms1. More
than 90% of drugs have poor solubility. It is estimated
that 40% of active new chemical entities (NCEs) identified
in combinatorial screening programs employed by many
pharmaceutical companies are poorly water soluble2.
After administering a drug orally, it firstly dissolves in
gastric and or intestinal fluids before it, and then
permeates the membranes of the GI tract to reach
systemic circulation. Therefore, a drug with poor aqueous
solubility will typically exhibit dissolution rate limited
absorption, and a drug with poor membrane permeability
will typically exhibit permeation rate limited absorption.
Hence, two areas of pharmaceutical research that focus
on improving the oral bioavailability of active agents
include: (i) enhancing solubility and dissolution rate of
poorly water-soluble drugs and (ii) enhancing
permeability of poorly permeable drugs3. Much of the
research that has been reported on solid dispersion
technologies involves drugs that are poorly water-soluble
and highly permeable to biological membranes as with
these drugs dissolution is the rate limiting step to
absorption. Hence, the hypothesis has been that the rate
of absorption in vivo will be concurrently accelerated with
an increase in the rate of drug dissolution. In the
Biopharmaceutical Classification System (BCS) drugs with
low aqueous solubility and high membrane permeability
4
are categorized as Class II drugs . Therefore, solid
dispersion technologies are particularly promising for
improving the oral absorption and bioavailability of BCS
Class II drugs.
Modified Noyes-Whitney equation5,6 gives some idea how
the dissolution rate of even very poorly soluble
compounds might be improved to minimize the
limitations to oral availability.
dC / dt =AD (Cs – C) / h
Where,
dC/dt is the rate of dissolution,
A is the surface area available for dissolution,
D is the diffusion coefficient of the compound,
Cs is the solubility of the compound in the dissolution
medium,
C is the concentration of drug in the medium at time t,
h is the thickness of the diffusion boundary layer adjacent
to the surface of the dissolving compound.
Surface area directly proportional to rate of dissolution, it
is increased by decreasing the particle size of drug or by
optimizing wetting characteristics. Particle size reduction,
salt formation, complexation and solubilization of drug in
solvent(s) also useful to increase dissolution, however,
there are limitations for this techniques. Administration
of the drug in the fed state may be an option to improve
the dissolution rate and also to increase the time
available for dissolution; the likely magnitude of the food
effect can be forecasted from dissolution tests in
biorelevant media7. Solid dispersion offers a various
preparation method and carrier option that allow the
flexibility when formulating oral delivery system for
poorly water soluble drugs.
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2. SOLID DISPERSION
Solid dispersion, a concept firstly introduced by Sekiguchi
and Obi8. The term “solid dispersions” refers to the
dispersion of one or more active ingredients in an inert
carrier in a solid state, frequently prepared by the melting
(fusion) method, solvent method or fusion solventmethod. The drug can be dispersed molecularly, in
amorphous particles (clusters) or in crystalline particles9.
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2.1.3.2. Discontinuous solid solutions
In the case of discontinuous solid solutions, the solubility
of each of the components in the other component is
limited. Due to practical considerations it has been
14
suggested by Goldberg et al. that the term `solid
solution' should only be applied when the mutual
solubility of the two components exceeds 5%.
2.1. Types of solid dispersion
2.1.1. Eutectic mixtures
A simple eutectic mixture consists of two compounds
which are completely miscible in the liquid state but only
to a very limited extent in the solid state. It is prepared by
rapid solidification of fused melt of two components that
show complete liquid miscibility but negligible solid-solid
8, 11
solution .
Figure 2: Phase diagram for a discontinuous solid
solution12.
2.1.3.3. Substitutional solid solutions:
Figure 1: Phase diagram for a eutectic system12.
Substitution is only possible when the size of the solute
molecules differs by less than 15% or so from that of the
solvent molecules15. Classical solid solutions have
crystalline structure, in which the solute molecules can
either substitute for solvent molecules in the crystal
lattice or fit into the intrsticies between the solvent
molecules.
2.1.2. Amorphous precipitation in crystalline matrix
This is similar to simple eutectic mixtures but only
difference is that drug is precipitated out in an
amorphous form13.
2.1.3. Solid solution
Solid solutions are comparable to liquid solutions,
consisting of just one phase irrespective of the number of
components. In the case of solid solutions, the drug's
particle size has been reduced to its absolute minimum
viz. the molecular dimensions14 and the dissolution rate is
determined by the dissolution rate of the carrier.
Classified according to their miscibility (continuous versus
discontinuous solid solutions) or second, according to the
way in which the solvate molecules are distributed in the
solvendum (substitutional, interstitial or amorphous).
Figure 3: Substitutional crystalline solid solution9.
2.1.3.4. Interstitial solid solutions:
In interstitial solid solutions, the dissolved molecules
occupy the interstitial spaces between the solvent
molecules in the crystal lattice. Solute molecule diameter
should be less than 0.59 times than that of solvent
molecular diameter16.
2.1.3.1. Continuous solid solutions
In a continuous solid solution, the components are
miscible in all proportions. Theoretically, this means that
the bonding strength between the two components is
stronger than the bonding strength between the
molecules of each of the individual components. Solid
solutions of this type have not been reported in the
pharmaceutical world till date.
Figure 4: Interstitial crystalline solid solution9.
2.1.4. Glass solution and suspensions:
Glass solutions are homogeneous glassy system in which
solute dissolves in glass carrier. Glass suspensions are
mixture in which precipitated particles are suspended in
glass solvent. Lattice energy is much lower in glass
13
solution and suspension .
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3. METHODS OF SOLID DISPERSION PREPARATION
Melting and solvent evaporation methods are the two
major processes of preparing solid dispersions17-20 .
3.1. Melting method
8
Sekiguchi et al. were the first to use a melting method
consisting of melting the drug within the carrier followed
by cooling and pulverization of the obtained product. In
the melting process, the molecular mobility of carrier is
high enough to change the drug’s incorporation21. The
use of high temperatures, and the fact that several drugs
can be degraded by the melting process, can be a
limitation of this method22.
3.1.1. Hot stage extrusion
Hot stage extrusion has in recent years gained wide
acceptance as a method of choice for the preparation of
solid dispersions. The hot stage extrusion process is highly
dependent on the physicochemical properties of the
compounds and their miscibility in the molten state. Hotstage extrusion consists of the extrusion, at high
rotational speed, of the drug and carrier, previously
mixed, at melting temperature for a small period of time.
Extrusion then collected after cooling at room
temperature and milled23,20,24. Moreover, it was observed
that solid dispersions of itraconazole/Intec SP1 prepared
by hot-stage extrusion presented itraconazole in a fully
glassy state, whereas it was only partially glassy in solid
dispersions prepared by spray drying20.
3.1.2. Melt agglomeration
Melt agglomeration allows the preparation of solid
dispersions in conventional high shear mixers. It is made
by adding the molten carrier containing the drug to the
heated excepients25. It is prepare by heating a mixture of
the drug, carrier and excipients to a temperature within
or above the melting range of the carrier26. It is also
possible to produce stable solid dispersions by melt
agglomeration in a rotary processor17.
3.2. Solvent evaporation method
The solvent evaporation method consists of the
solubilization of the drug and carrier in a volatile solvent
27-29
that is later evaporated . In this method, the thermal
decomposition of drugs or carriers can be prevented,
since organic solvent evaporation occurs at low
temperature19. A basic process of preparing solid
dispersions of this type consists of dissolving the drug and
the polymeric carrier in a common solvent, such as
ethanol, chloroform, mixture of ethanol and
dichloromethane. Normally, the resulting films are
pulverized and milled28,30.
3.2.1. Spray-drying
Spray-drying is one of the most commonly used solvent
evaporation procedures in the production of solid
20, 31, 32
dispersions. It consists of dissolving
or suspending
the drug and carrier, then spraying it into a stream of
heated air flow to remove the solvent20, 31. Due to the
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large specific surface area offered by the droplets, the
solvent rapidly evaporates and the solid dispersion is
formed within seconds, which may be fast enough to
33
prevent phase separation. Van Drooge et al. prepared
an alternative solid dispersion by spraying a povidone and
diazepam solution into liquid nitrogen, forming a
suspension that was then lyophilized.
3.2.2. Freeze-drying
This process consists of dissolving the drug and carrier in
a common solvent, which is immersed in liquid nitrogen
until it is fully frozen. Then, the frozen solution is further
lyophilized33,21. Although it is concluded in literature that
this is a promising and suitable technique to incorporate
drug substances in stabilizing matrices34, the technique is
poorly exploited for the preparation of solid dispersions35.
An important advantage of freeze drying is that the drug
is subjected to minimal thermal stress during the
formation of the solid dispersion. However, the most
important advantage of freeze drying is that the risk of
phase separation is minimized as soon as the solution is
vitrified.
3.2.3. Supercritical fluid method
Supercritical fluid methods are mostly applied with
carbon dioxide (CO2), which is used as either a solvent for
drug and matrix or as an anti-solvent36,37. This technique
consists of dissolving the drug and the carrier in a
common solvent that is introduced into a particle
formation vessel through a nozzle, simultaneously with
CO2. When the solution is sprayed, the solvent is rapidly
extracted by the SCF, resulting in the precipitation of solid
dispersion particles on the walls and bottom of the
vessel19. The use of processes using SCF reduces particle
size, residual solvent content, without any degradation
and often results in high yield38, 17, 39.
3.2.4. Co-precipitation method
Co-precipitation is a recognized technique for increasing
the dissolution of poorly water soluble drugs, so as to
consequently improve bioavailability. In this method nonsolvent is added drop wise to the drug and carrier
solution, under constant stirring. In the course of the nonsolvent addition, the drug and carrier are co-precipitated
to form micro particles. At the end, the resulted micro
particle suspension is filtered and dried40. The required
quantity of polymer and the drug were mixed and then
solvent was added to obtain clear solution. The Solution
was first dried under vacuum at room temperature and
kept inside incubator (370c) for 12 hrs. Finally it was
passed through sieves41.
3.2.5. Dropping method
This technique may overcome some of the difficulties
inherent in the other method and developed by Ulrich et
12
al. to facilitate the crystallization of different chemicals,
is a new procedure for producing round particles from
melted solid dispersions A solid dispersion of a melted
drug carrier mixture is pipetted and then dropped onto a
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Volume 8, Issue 2, May – June 2011; Article-012
plate, where it solidifies into round particles. The size and
shape of the particles can be influenced by factors such as
the viscosity of the melt and the size of the pipette. The
dropping method does not use organic solvents and,
therefore, has none of the problems associated with
solvent evaporation. This method also avoids the
pulverization, sifting and compressibility difficulties42.
4. CARRIERS USED IN SOLID DISPERSION
4.1. Polyethylene glycol (PEG)
4.1.1. General characteristics of PEGs: Polyethylene
glycols (PEG) are polymers of ethylene oxide, having a
molecular weight (MW) in the range 200- 300000. For the
manufacture of solid dispersions and solutions, PEGs with
molecular weights of 1500-20000 are usually employed.
As the MW increases, so does the viscosity of the PEG. A
particular advantage of PEGs for the formation of solid
dispersions is that they also have good solubility in many
organic solvents. The melting point of the PEGs of interest
lies under 650C in every case (e.g. the m.p. of PEG 1000 is
30-400C, the m.p. of PEG 4000 is 50-580C and the m.p. of
PEG 20000 is 60-630C)43. These relatively low melting
points are advantageous for the manufacture of solid
dispersions by the melting method. Dissolution rate of a
relatively soluble drug like aspirin can be improved by
formulating a solid dispersion in PEG 600044.
4.1.2. Influence of the PEG chain length: PEGs of MW
4000-6000 are the most frequently used for the
manufacture of solid dispersions, because in this MW
range the water solubility is still very high, but hygroscopy
is not a problem and the melting points are already over
500C. If PEG with low a MW is used, the product changes
it’s consistency and gives a sticky consistency that is
difficult to formulate product45. PEGs with higher MW
have also been used with success, products containing
PEG 800046 and 1000047 showed enhanced dissolution
rates compared to the pure drug. Phenylbutazone/PEG
solid dispersions indicated that the release is dependent
on the PEG MW48.
4.1.3. Influence of drug/PEG ratio: If the percentage of
the drug is too high, it will form small crystals within the
dispersion rather than remaining molecularly dispersed.
On the other hand, if the percentage of the carrier is very
high, this can lead to the complete absence of crystallinity
of the drug and thereby enormous increases in the
solubility and release rate of the drug49
4.2. Polyvinylpyrrolidone (PVP)
4.2.1. General characteristics of PVP: Polymerization of
vinylpyrrolidone leads to polyvinylpyrrolidone (PVP) of
molecular weights ranging from 2500 to 3000000. These
can be classified according to the K value, which is
calculated using Fikentscher's equation50. The glass
transition temperature of a given PVP is dependent not
only on its MW but also on the moisture content. In
general, the glass transition temperature (Tg) is high; for
0 51
example, PVP K25 has a Tg of 155 C . For this reason
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PVPs have only limited application for the preparation of
solid dispersions by the hot melt method. PVP is suitable
for the preparation of solid dispersions by the solvent
method. Similarly to the PEGs, PVPs have good water
solubility and can improve the wettability of the
dispersed compound in many cases. Improved wetting
and thereby an improved dissolution rate from a solid
dispersion in PVP has been demonstrated for flufenamic
acid52.
4.2.2. Influence of the PVP chain length: The aqueous
solubility of the PVPs becomes poorer with increasing
chain length and a further disadvantage of the high MW
PVPs is their much higher viscosity at a given
concentration50.
4.2.3. Drug/PVP ratio: Solid dispersion prepared with
high proportions of PVP tend to exhibit a higher drug
solubility and release rate than those with high
proportions of drug. For albendazole, for example, it has
been shown that an increase in the %PVP in the
dispersion leads to an increase in the release rate53.
When the carrier comprised 81% of the dispersion, no
crystalline areas could be detected and the release rate of
the compound was rapid. Interestingly, when the %carrier
was further increased, the release rate became slower. In
the case of piroxicam/PVP solid dispersions54, the release
rate increased with the %PVP up till a ratio of drug/carrier
of 1:4, after which it fell again (at ratios of 1:5 and 1:6).
4.3. Polyvinylalcohol (PVA), crospovidone (PVP-CL),
polvinylpyrrolidone-polyvinylacetate copolymer (PVPPVA): These three polymers belong to the polyvinyl
group.
Whereas
polyvinylalcohol
(PVA)
and
vinylpyrrolidone/vinylacetate (PVP-PVA) copolymers are
both water soluble, crospovidone swells when dispersed
in water. The use of PVA/PVP copolymers as carriers in
solid dispersions has been shown to lead to enormous
increases in the drug release rate. Studies with the
cytostatic drug HO-221 showed that the PVA/PVP solid
dispersed not only dissolved 25 times faster than the drug
powder, but also enhanced the bioavailability in beagles
55
by a factor of 3.5 . Even though crospovidone does not
dissolve in water, it can also be used as a carrier to
improve drug release rates. For example, a 1:2 ratio of
furosemide to crospovidone led to an increase in the
dissolution rate by a factor of 5.856, in comparison with
either the drug powder or a physical mixture of
furosemide with crospovidone.
4.4. Cellulose derivatives:
4.4.1. General characteristics of cellulose derivatives:
Celluloses are naturally occurring polysaccharides that are
ubiquitous in the plant kingdom. They consist of high
molecular weight unbranched chains, in which the
saccharide units are linked by ß-1,4-glycoside bonds. By
appropriate alkylation, the cellulose can be derivatized to
form
methyl(MC),
hydroxypropyl(HPC),
hydroxypropylmethyl- (HPMC) and many other semisynthetic types of cellulose. Since each glucose unit has
three hydroxyl groups that can be derivatized, the
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average substitution grade (SG). A further possibility for
derivatization is the esterification of the cellulose to form
compounds such as cellulose acetate phthalate (CAP) and
68
hydroxypropylmethylcellulose phthalate (HPMCP) .
4.4.2. Hydroxypropylmethylcellulose (HPMC): HPMCs are
mixed ethers of cellulose, in which 16.5-30% of the
hydroxyl groups are methylated and 4-32% are
derivatized with hydroxypropyl groups. The molecular
weight of the HPMCs ranges from about 10000 to
1500000 and they are soluble in water and mixtures of
ethanol with dichloromethane and methanol with
dichloromethane57. A poorly soluble weak base with
incomplete bioavailability showed that the release rate
and the bioavailability in beagles could be improved
through preparation of a solid dispersion in HPMC58.
Other drugs which exhibit faster release from solid
dispersion in HPMC include the poorly soluble weak acids
59
and benidipine .
4.4.3.
Hydroxypropylcellulose
(HPC):
Hydroxypropylmethylcellulose exhibits good solubility in a
range of solvents, including water (up till 400C), ethanol,
methanol and chloroform. The average MW of the HPCs
ranges from 37000 (Type SSL) to 1150000 (Type H)60. The
release rate improved as the proportion of HPC was
increased and when lower MW HPCs were used as the
carrier.
4.4.4. Carboxymethylethylcellulose (CMEC): CMEC also
belongs to the cellulose ethers, but unlike many of the
others it is resistant to dissolution under gastric (acidic)
conditions. It dissolves readily at pH values above 5-6,
with lowest dissolution pH being dependent on the grade
of the CMEC. Amorphous solid dispersions of nifedipine
and spironolactone show enormous increases in the
dissolution rate of the drug at pH values of 6.861.
4.4.5.
Hydroxypropylmethylcellulose
phthalate
(HPMCP): HPMCPs are cellulose esters which are often
used as enteric coatings. Depending on the grade, they
dissolve first at pH 5 (HP 50) or pH 5.5 (HP 55). Their
solubility in organic solvents is also type-dependent. Their
62
MWs range from 20000 to 2000000 .
4.5. Polyacrylates and polymethacrylates
Polyacrylates and polymethacrylates are glassy
substances that are produced by the polymerization of
acrylic and methacrylic acid, and derivatives of these
polymers such as esters amides and nitriles. Commonly
they are referred today the trade name Eudragit65.
Eudragit E is often used to improve the release rate since
it is soluble in buffer solutions at pH values up to 5 and
swells at higher pH, while Eudragit L can be used when it
is desirable to avoid release in the stomach. When
benipidine was formulated as a coevaporate with
Eudragit E, the rate of dissolution was much higher than
59
from the pure drug powder .
ISSN 0976 – 044X
4.6. Urea
In one of the first bioavailability studies of solid
dispersions, it was shown that sulphathiazole was better
8
absorbed in rabbits when given as a eutectic with urea .
Although urea is not often used as a carrier these days. In
the case of ursodeoxycholic acid the release rate from
urea dispersions prepared by the hot melt method was
faster than from other carriers studied, including PEG
600065.
4.7. Sugar, polyols and their polymers
Chitosan a derivative of the polysaccharide chitin which is
formed by deacetylation at the N position has also been
used as a carrier in solid dispersions. Both chitosan and
its salt form, chitosan glutamate, were able to improve
the release of nifedipine by a factor of two to three
68
compared to the drug powder .
4.8. Emulsifiers
Two mechanisms are possible here for release behavior of
drug: improvement of wetting characteristics and
solubilization of the drug. Bile salts and their derivatives
are natural surfactants that are built from a steroidal
skeleton in the liver and which are important to the
emulsification of fats and oils in the diet. As with other
surfactants, they can enhance the wetting and solubility
of many lipophilic substances, leading to an increase in
the dissolution rate66.
4.9. Organic acids and their derivatives
Organic acids such as succinic acid and citric acid have
also been used as carriers in solid dispersions, originally
to enhance the release rate of griseofulvin[10].
4.10. Surface active agents67
Surface-active agents are substances that at low
concentrations adsorb onto the surfaces or interfaces of a
system and alter the surface or interfacial free energy and
the surface and the interfacial tension. Surface-active
agents have a characteristic structure, possessing both
polar (hydrophilic) and non-polar (hydrophobic) regions in
the same molecule. The surface active carriers are said to
be amphipathic in nature. , surface active carriers may be
included to improve the efficacy or the bioperformance of
drug. The properties of surfactant are such that they can
alter the thermodynamic activity, solubility, diffusion,
disintegration, and dissolution rate of a drug.
Figure 5: Shows the advantage of a surface-active carrier
over a non-surface-active one in the dissolution of drug
from a capsule formulation67.
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15
5. ADVANTAGES OF SOLID DISPERSION
1. Improving drug bioavailability by changing their water
solubility has been possible by solid dispersion.
2. Solid dispersions are more efficient than these particle
size reduction techniques, since the latter have a particle
size reduction limit around 2–5 mm which frequently is
not enough to improve considerably the drug solubility or
drug release in the small intestine.
3. Increase in dissolution rate & extent of absorption and
reduction in Pre systemic metabolism.
4. Transformation of liquid form of drug into solid form.
5. Parameters, such as carrier molecular weight and
composition, drug crystallinity and particle porosity and
wettability, when successfully controlled, can produce
improvements in bioavailability.
6. DISADVANTAGES OF SOLID DISPERSION
The resulting enhanced surface area produces
higher dissolution rate and bioavailability of poorly watersoluble drugs. Carriers with or without any surface
activity, when used, can significantly increase the
wettability properties of drugs. The increase in porosity
also depends on the carrier properties, for instance, solid
dispersions containing linear polymers produce larger and
more porous particles than those containing reticular
polymers and, therefore, result in a higher dissolution
rate and increases the solubility of poorly water soluble
drug. Solid dispersion has also been used to produce
sustained release microsphere using tedious methods.
New optimized techniques are also useful in the
industries.
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15
1. Moreover, most of the polymers used in solid
dispersions can absorb moisture, which may result in
phase separation, crystal growth or conversion from the
amorphous to the crystalline state or from a metastable
crystalline form to a more stable structure during storage.
This may result in decreased solubility and dissolution
rate
2. Drawback of solid dispersions is their poor scale-up for
the purposes of manufacturing.
7. CHARACTERIZATION OF SOLID DISPERSIONS68
The most important methods which are use for
characterization are thermo analytical, X-ray diffraction,
infrared spectroscopy and measurement of the release
rate of the drug.
Methods for the characterization of solid dispersions are
as following
1. Dissolution testing.
2. Thermo analytical methods: differential thermo
analysis and hot stage microscopy.
3. Calorimetric analysis of the solution or melting
enthalpy for calculation of entropy
change.
4. X-Ray diffraction.
5. Spectroscopic methods, e.g. IR spectroscopy, NMR
spectroscopy.
6. Microscopic methods including polarization microscopy
and scanning electron microscopys.
8. CONCLUSION
Solid dispersion systems as extremely useful tool in
improving the dissolution and solubility enhancement
properties of poorly water-soluble drugs. When the solid
dispersion is exposed to aqueous media, the carrier
dissolves and the drug releases as fine colloidal particles.
10. Chiou WL, Riegelman S, Preparation and dissolution
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rates and gastrointestinal absorption of drugs via solid
solutions and eutectic mixtures II - experimental evaluation
of a eutectic mixture: urea-acetaminophen system, J.
Pharm. Sci. 55,1966, 482-487.
12. Castellan GW, Physical Chemistry, Addison-Wesley, Menlo
Park, CA, 1983, 324-336.
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13. Swarbrick J, Encyclopedia of Pharmaceutical Technology,
ed 3, 2006, 775-777.
14. Goldberg AH, Gibaldi M, Kanig JL, Increasing dissolution
rates and gastrointestinal absorption of drugs via solid
solutions and eutectic mixtures. I. Theoretical
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